Tuberous sclerosis complex: Evaluation and diagnosis

INTRODUCTION — Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin. The expression of the disease varies substantially. The diagnosis of TSC can be made clinically or through genetic testing.

The clinical evaluation and diagnosis of TSC will be reviewed here. Other aspects of TSC are discussed elsewhere:

●(See "Tuberous sclerosis complex: Genetics and pathogenesis".)

●(See "Tuberous sclerosis complex: Clinical features".)

●(See "Tuberous sclerosis complex: Management and prognosis".)

●(See "Renal manifestations of tuberous sclerosis complex".)

●(See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

WHEN TO SUSPECT TSC — Certain clinical scenarios should raise suspicion for the diagnosis of TSC [1]:

●The prenatal detection of cardiac rhabdomyomas (see "Tuberous sclerosis complex: Clinical features", section on 'Cardiovascular manifestations')

●The detection of hypomelanotic skin macules (see "Tuberous sclerosis complex: Clinical features", section on 'Dermatologic manifestations')

●The onset of seizures, particularly infantile spasms (see "Tuberous sclerosis complex: Clinical features", section on 'Seizures and epilepsy')

●An evaluation for autism with or without cognitive disability (see "Tuberous sclerosis complex: Clinical features", section on 'TSC-associated neuropsychiatric disorders (TAND)')

The classic TSC diagnostic triad of seizures, intellectual disability, and facial angiofibromas (Vogt triad) occurs in less than one-third of patients with TSC [2]. Thus, clinicians must be familiar with the full spectrum of TSC-associated diagnostic features. Furthermore, there is a range of phenotypes between and within families that includes patients with normal to severely impaired neurologic function [3,4]. In particular, a parent who has somatic mosaicism for a pathogenic variant may have mild features. However, an offspring who inherits this pathogenic variant will not be mosaic and may have much earlier onset of symptoms and more severe symptoms than the parent.

All of the clinical features of TSC may not be apparent in the first year of life. Thus, a child is often diagnosed initially with possible or probable TSC and later diagnosed with definite TSC after additional features are identified. Rather than waiting for more features to emerge, the diagnosis of definite TSC can be confirmed in this setting by molecular genetic testing, which reveals a disease-causing TSC1 or TSC2 pathogenic variant in 85 to 90 percent of individuals who eventually meet clinical diagnostic criteria for TSC. (See 'Genetic criteria' below and 'Genetic testing' below.)

INITIAL EVALUATION

History — The initial screening evaluation should confirm the diagnosis by identifying clinical features of TSC. The history should focus on symptoms associated with the disorder. (See "Tuberous sclerosis complex: Clinical features" and 'Diagnosis' below.)

The parents and caregivers should be questioned specifically about the presence or absence of seizures or developmental delay, which are often associated with TSC but are not diagnostic criteria for the disorder. A detailed family history also should be obtained to detect possible symptoms of TSC. International TSC guidelines recommend obtaining a three-generation family history to assess for additional family members at risk for TSC [5]. When possible, parents and siblings should be examined for characteristic signs.

Examination — The examination should focus on the skin and neurologic systems:

●The skin should be thoroughly examined for the characteristic dermatologic features of TSC, including hypomelanotic macules, fibroadenomas, shagreen patches, and the distinctive brown fibrous plaque often present on the forehead. The skin manifestations are most apparent on the face. Use of a Wood's lamp (ultraviolet [UV] light) may facilitate the identification of hypomelanotic macules. The presence or absence of each of the major dermatologic features should be specifically recorded in the medical record. Parents of a child suspected of having TSC should undergo a similar examination. (See "Tuberous sclerosis complex: Clinical features", section on 'Dermatologic manifestations'.)

●A careful neurologic examination should be performed to look for evidence of hydrocephalus, papilledema, or focal neurologic deficits suggestive of another disorder.

●Ophthalmic evaluation may identify the characteristic TSC lesions, which include retinal hamartomas, hypomelanotic choroidal lesions, and lid angiofibromas. (See "Tuberous sclerosis complex: Clinical features", section on 'Ophthalmic manifestations'.)

Imaging — Cranial magnetic resonance imaging (MRI) should be performed to detect cortical glioneuronal hamartomas, subependymal nodules, subependymal giant cell astrocytomas (also known as subependymal giant cell tumors), or cerebral white matter abnormalities.

Imaging with MRI of the abdomen or kidney ultrasound is indicated to evaluate for the presence of renal angiomyolipomas or renal cysts.

Electroencephalography — An electroencephalogram (EEG) should be obtained in children with a history of seizures or spells suspicious for seizures. (See "Tuberous sclerosis complex: Clinical features", section on 'Seizures and epilepsy'.)

Genetic testing — We recommend molecular genetic testing for disease-causing pathogenic variants in the TSC1 and TSC2 genes for all individuals with suspected TSC, where available, to support a clinical diagnosis.

●Method – Because of the wide spectrum of mechanisms leading to pathogenic variants, full sequencing plus analysis for small- and large-scale deletions of both TSC1 and TSC2 is necessary for a comprehensive molecular diagnosis of patients with suspected TSC [6].

●Utility – A positive test for a pathogenic TSC1 or TSC2 variant in nonlesional tissue, usually from a whole blood sample, is sufficient to make a definite diagnosis of TSC independent of clinical findings [7]. However, genetic testing is important for all patients with a suspected diagnosis of TSC. Since mutation detection is not 100 percent sensitive, a molecular genetic diagnosis is not required to confirm the diagnosis in patients who fulfill clinical criteria for definite TSC. (See 'Clinical criteria' below.)

•We offer genetic testing at the initial visit. Genetic testing is particularly important for patients with possible TSC who do not meet the criteria for definite TSC (see 'Clinical criteria' below), since the various manifestations of TSC can develop over time due to the age-dependent penetrance of some features of TSC and the possibility of somatic mosaicism. Genetic confirmation of TSC in individuals who do not yet fulfill clinical criteria is helpful for directing surveillance and management [7]. (See "Tuberous sclerosis complex: Management and prognosis".)

•Genetic testing is helpful for family studies (eg, defining disease status and reproductive risks for relatives) and for preimplantation or prenatal diagnosis. (See 'Parental evaluation' below and 'Preimplantation and prenatal testing' below.)

•Genetic testing is also useful in definite TSC given differences in phenotypic presentation.

Disease-causing pathogenic variants in the TSC1 or TSC2 genes can be detected in 85 to 90 percent or more of patients who meet the diagnostic criteria. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Molecular genetic testing'.)

●Negative test – A negative genetic test does not exclude the diagnosis of TSC in an apparently affected individual, since 10 to 15 percent of individuals with TSC have no pathogenic variant identified by standard genetic testing [7]. Furthermore, a positive test does not predict either the severity or nature of the disease complications.

One cause of a negative genetic test is the presence of somatic mosaicism, which is estimated to occur in 2 to 10 percent of de novo cases of TSC [8]. In somatic mosaicism, the pathogenic variant in the TSC1 or TSC2 gene is not present in all cells. This occurs when the pathogenic variant is present in the developing embryo and results in a variable mixture of normal and affected cells in different tissues. In individuals with mosaicism, genetic testing performed on deoxyribonucleic acid (DNA) from blood leukocytes may be normal, depending upon the degree of mosaicism in the blood [8].

Other causes of a negative genetic test may include splice-region variants or other variants that may not be tested for in routine sequencing analyses.

DIAGNOSIS — Diagnostic criteria from the International Tuberous Sclerosis Complex Consensus Conference (see 'Genetic criteria' below and 'Clinical criteria' below) allow for the diagnosis of TSC based upon genetic testing results and/or clinical findings [7].

Genetic criteria — The identification of either a TSC1 or TSC2 pathogenic variant from nonlesional tissue is sufficient to make a definite diagnosis of TSC, regardless of clinical findings [7]. A pathogenic variant is defined as a variant that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, nonsense variant), prevents protein synthesis (eg, large deletion), or impairs protein function, as established by functional assessment and clinical correlation.

Clinical criteria — The clinical diagnostic criteria for TSC include 11 major and 7 minor features [7].

●Major features – The following are major clinical features of TSC [7]:

•Hypomelanotic macules (≥3, at least 5 mm diameter)

•Angiofibromas (≥3) or fibrous cephalic plaque

•Ungual fibromas (≥2)

•Shagreen patch

•Multiple retinal hamartomas

•Multiple cortical tubers and/or radial migration lines

•Subependymal nodules (≥2)

•Subependymal giant cell astrocytoma

•Cardiac rhabdomyoma

•Lymphangioleiomyomatosis (LAM)*

•Angiomyolipomas (≥2)*

*A combination of LAM and angiomyolipomas without other features does not meet criteria for a definite diagnosis. Some females have angiomyolipomas of the kidney associated with pulmonary lymphangioleiomyomatosis but no other TSC-related features [9]. These patients do not have an increased risk of having an affected child. Therefore, they are not considered to have TSC. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

●Minor features – The following are minor clinical features of TSC [7]:

•"Confetti" skin lesions (1 to 2 mm hypomelanotic macules)

•Dental enamel pits (≥3)

•Intraoral fibromas (≥2)

•Retinal achromic patch

•Multiple renal cysts

•Nonrenal hamartomas

•Sclerotic bone lesions

●Diagnostic certainty – The diagnostic certainty of TSC depends upon the number of major and minor features [7]:

•Definite TSC requires two major features or one major and two or more minor features.

•Possible TSC requires either one major feature or two or more minor features.

A pathogenic variant in TSC1 or TSC2 confirms the genetic diagnosis of TSC, regardless of clinical diagnostic certainty [7].

DIFFERENTIAL DIAGNOSIS — Many TSC features may occur in isolation or as manifestations of another disorder [10].

●Seizures – The differential diagnosis of seizures and epilepsy is broad. Infantile spasms are the most common type of seizures in children less than one year of age with TSC; focal seizures are the most common type in older children. In addition to TSC, causes of infantile spasms include congenital infections, perinatal and postnatal brain insults, brain malformations, Aicardi syndrome, other genetic disorders, inborn errors of metabolism, and other neurocutaneous disorders (eg, linear nevus sebaceous syndrome, incontinentia pigmenti, pigmentary mosaicism of Ito, Sturge-Weber syndrome, and neurofibromatosis type 1). A minority of infantile spasms are of unknown cause. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis" and "Infantile epileptic spasms syndrome: Clinical features and diagnosis".)

●Skin lesions – Hypomelanotic macules may occur in otherwise healthy individuals as isolated lesions [11] and are also seen in association with various dermatologic conditions including vitiligo, nevus depigmentosus, and Vogt-Koyanagi-Harada syndrome [10]. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

Ungual fibromas can occur because of trauma, but they generally occur as single lesions when traumatic in origin [10].

●Heart – Most cases of cardiac rhabdomyomas are associated with TSC, but some cases present in isolation. (See "Cardiac tumors", section on 'Rhabdomyomas'.)

●Kidney – The differential diagnosis of renal angiomyolipomas is reviewed separately. (See "Renal manifestations of tuberous sclerosis complex", section on 'Differential diagnosis'.)

●Lung – The differential diagnosis of cystic lung disease in patients with TSC is similar to that in sporadic lymphangioleiomyomatosis, as discussed elsewhere. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Differential diagnosis'.)

FAMILY SUPPORT AND EVALUATION

Counseling — The diagnosis of a child with TSC has a major impact on the family [12]. Counseling should be provided for patients, families, and caregivers. It should include information on the inheritance of the disorder, genetic testing results, prognosis, and psychosocial adjustment. The progressive nature of the disease and its clinical manifestations and complications should be addressed.

International TSC guidelines recommend that first-degree relatives of affected patients with TSC should be offered clinical assessment [7]. In addition, they should be offered genetic testing if a pathogenic variant has been identified in the index case.

The genetics of TSC, including potential recurrence risk in other offspring, should be explained to the parents of affected children. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Genetics'.)

Specific counseling may be warranted for adolescents with TSC who face issues with self-esteem and the psychosocial impact of this condition.

Organizations such as the Tuberous Sclerosis Alliance (United States) and the Tuberous Sclerosis Association (United Kingdom) provide information about the disorder and general support. Referral of the family to a local chapter can be helpful.

Parental evaluation — When the diagnosis is made in a child with no family history of the disorder, both parents should be evaluated. This evaluation should include:

●Testing for the familial TSC pathogenic variant if a TSC1 or TSC2 pathogenic variant has been identified in the child (algorithm 1)

●A thorough examination of the skin (in normal light and with a Wood's lamp)

●Ophthalmic examination

●Cranial MRI (preferable) or computed tomography (CT) scan

●MRI of the abdomen or kidney ultrasound to evaluate for the presence of renal angiomyolipomas or renal cysts

Although TSC is an autosomal dominant condition, only a minority of patients have a known family history of TSC. The remaining cases represent new pathogenic variants or mosaicism in the affected parent. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Genetics'.)

Parents who are negative on genetic testing for the TSC pathogenic variant found in their affected child may still carry this variant as either a low-level somatic or germline mosaic. Thus, they may be at risk for having future children affected with TSC. It is very important to make this point clear to parents.

Normal intelligence and the absence of a history of seizures in the parents do not exclude the diagnosis of TSC.

The importance of determining whether a parent is affected lies in providing appropriate follow-up for the parent (eg, screening for kidney disease) and in providing an appropriate risk estimate of having a subsequent child with TSC. Because TSC is inherited in an autosomal dominant pattern, the risk of this disorder in each offspring of an affected parent is 50 percent. However, if neither parent meets the clinical criteria for TSC, the risk of the parents having another child with TSC is approximately 2 percent [8]. This risk is due to gonadal mosaicism, which occurs when either parent carries the pathogenic variant in more than one egg or sperm cell [8,13]. An adult who is mosaic for a severe pathogenic variant (eg, a truncating variant in TSC2) may be mildly affected but has a 2 to 50 percent chance of transmitting the variant to their child (it is not clinically possible to assess the degree of mosaicism in a gonad). However, any offspring who inherit this variant will not be mosaic; they will carry the pathogenic variant in every cell of the body and may be severely affected. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'De novo versus familial TSC'.)

Preimplantation and prenatal testing — Reproductive decisions by couples are facilitated by appropriate genetic counseling. Prospective parents should be aware that TSC exhibits wide clinical variability within families and that establishing the diagnosis prenatally cannot predict the severity or outcome. The couple should also understand that their risk of having an affected child could be substantially lowered by use of reproductive technologies, including preimplantation genetic diagnosis, if the pathogenic variant is known, or sperm or oocyte donation, depending upon which parent is affected.

For families where a specific TSC pathogenic variant is identified, preimplantation genetic diagnosis involves single cell analysis after biopsy of an embryo obtained through in vitro fertilization and subsequent implantation of embryos at low risk of carrying the pathogenic variant [14]. Prenatal testing for TSC1 or TSC2 pathogenic variants of specimens obtained during pregnancy through either chorionic villus sampling or amniocentesis is also available; it should be offered to parents where a pathogenic variant has been identified in their child, even those with apparently "de novo" pathogenic variants, in view of the high rate of gonadal mosaicism in this condition.

SUMMARY AND RECOMMENDATIONS

●Suspicion for TSC – The diagnosis of tuberous sclerosis complex (TSC) may be suspected in certain clinical scenarios, including prenatal detection of cardiac rhabdomyomas, the presence of hypomelanotic skin macules, the onset of seizures (particularly infantile spasms), and suspicion for autism. (See 'When to suspect TSC' above.)

●Initial evaluation

•History – The history should focus on identifying the clinical features of TSC. (See 'History' above.)

•Examination – The examination should focus on the skin along with neurologic and ophthalmic evaluations. (See 'Examination' above.)

•Imaging – Cranial MRI is optimal to detect cortical glioneuronal hamartomas, subependymal nodules, subependymal giant cell tumors, or cerebral white matter abnormalities. MRI of the abdomen or kidney ultrasound is indicated to evaluate for the presence of renal angiomyolipomas or renal cysts. (See 'Imaging' above.)

•EEG – An EEG should be obtained if there is a history of seizures or suspicion for seizures. (See 'Initial evaluation' above and 'Electroencephalography' above.)

●Genetic testing

•For all individuals with suspected TSC without a family history, we suggest sequencing and dosage analysis of the TSC1 and TSC2 genes.

•For individuals with suspected TSC and a family history of TSC in a first-degree relative, genetic testing can be focused on testing for the familial variant.

Genetic testing is useful for confirming the diagnosis in individuals with possible TSC, for reproductive planning, and for identifying at-risk family members. However, a negative genetic test does not exclude the diagnosis of TSC in an apparently affected child, particularly due to the possibility of mosaicism. (See 'Genetic testing' above.)

●Diagnostic criteria – The diagnostic criteria for TSC are outlined above. The identification of a pathogenic variant in either TSC1 or TSC2 is sufficient to make a definite diagnosis of TSC. (See 'Diagnosis' above.)

●Counseling – Counseling should be provided for patients with TSC and their families and caregivers. It should include information on the inheritance of the disorder, genetic testing results, prognosis, and psychosocial adjustment. (See 'Counseling' above.)

●Parental evaluation – When the diagnosis is made in a child with no family history of the disorder, both parents should be carefully evaluated for features of TSC and offered genetic testing if a causative variant has been identified. (See 'Parental evaluation' above.)